6-methylene-steroids and process



United States Patent 0 fi-METHYLENE-STEROIDS AND PROCESS Frank B. Colton, Chicago, 111., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed Apr. 28,1960, Ser. No. 25,230

3 Claims. (Cl. 2'60397.4)

The present invention is concerned with novel steroidal compounds substituted at the 6-position with a methylene radical, and with a novel process for'the production thereof. These derivatives can be represented by the structural formulae CH: CH:

and

radicals, R being a lower. alkyl radical; and R is hydrogen or a lower alkanoyl radical.

The lower alkyl radicals represented by R are typi enol alkyl ether of the appropriate 6-methyl-4-en-? one ice which manganese dioxide. This process can be illustrated using the following partial structural formulae It has been determined as a further embodiment of the instant invention that manganese dioxide prepared by a special procedure is unusually active in the conduct of the herein-disclosed process. This special procedure is described below:

An aqueous solution of manganous sulfate is heated on a steam bath and an alkali metal premanganate, typically potassium permanganate, is slowly added until the presence of a small excess is made evident by that fact that a purple color persists for 15 minutes. The mixture is then filtered and the precipitate is thoroughly washed with water. The manganese dioxide formed is not washed with an organic solvent as is frequently suggested in the literature, but is rather dried at 70 for several hours.

in the presence of the corresponding alkanol and an acid catalyst. By this process, for example, 17a-acetoxy- 6 methylpregn 4 ene 3,20 dione, 17a (2 carboxyethyl)-l7fi-hydroxy-6-methylandrost-4-en-3-one lactone, or 21-acetoxy-17a-hydroxy-6-methylpregn-4-ene-3, 11,20-trione is treated with ethyl orthoformate and etha- 1101 in the presence of p-toluenesulfonic acid to afford 17a-acetoxy-3 6 methylpregn-a 3,5 dien 20 one, 1711 5 (2 carboxylethyl) 3 ethoxy 17,8 hydroxy 6- methylandrosta-3,5 diene lactone, or 21 acetoxy 3- ethoxy-l7u-hydroxy-6-methylpregna-3,5 diene 3,11,20- trione, respectively.

The preparation of the instant 6-methylene compounds by manganese dioxide oxidation of the aforementioned enol alkyl ethers can be conducted at temperatures. of 10-60", although the preferred operating range is room temperature, i.e. l5-30. The reaction time can vary from 15 minutes to 2 hours. The process is preferably conducted in an inert non-polar organic solvent medium.

Typical suitable solvents are benzene, toluene, xylene, methylene chloride, and carbon tetrachloride. This process-is exemplifiedby the reaction of the aforementioned 17oz acetoxy 3 ethoxy 6 methylpregna 3,5 dien- 20-one, 17a-(2-carboxyethyl) -3-ethoxy-17p hydroxy 6- methylandrosta 3,5 diene lactone, or 21 acetoxy 3 ethoxy 17cc hydroxy 6 methylpregna 3,5 diene- 3,11,20-trione with manganese dioxide in benzene to produce 1Za-acetoXy-6-methylenepregn-4 ene 3,20 dione, 17w (.Z-carboxyethyl)-17fl-hydroxy-6-methylene androst- 4-en-3-one lactone, and 21 acetoxy 11a hydroxy 6 wherein R is a lower alkyl radical, are progestational agents which lack the potent. side-effects, for example, anabolic, androgenic, anti-ovulatory and neoglycogenetic, exhibited by prior art progestational compositions.

The instant compounds of structural formula are useful as a result of their anti-inflammatory properties, and possess the advantage over prior art agents of that type in that they lack certain potent side eflects, for example neoglycogenetic and eosinopenic.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In

these examples temperatures are given in degrees centi- 1 grade C.).' Quantities of materials are expressed in parts by weight unless'otherwise noted.

I Example 1 Example 2 By submitting an equivalent quantity of 6u-methyl- 17a-propionoxypregn-4-ene-3,20-dione to the processes described in Example 1, 3-ethoxy-6a-methyl-17a-pro- To a solution of one part of 17oi-acetoxy-3-ethoxy-6amethylpregna-3,5-dien-20-one in 44 parts of benzene is added 5 parts of manganese dioxide, and the resulting reaction mixture is stirred for about 40 minutes. The insoluble material is removed by filtration and washed on the filter with benzene. Concentration of the filtrate to dryness under nitrogen affords a crystalline residue. Recrystallization of this residue from methanol afiords 17a-acetoxy 6 methylenepregn-4-ene-3,20-dione, M.P. about 248251. The ultravoilet absorption spectrum of this substance exhibits a maximum at about 262-263 millirnicrons with an extinction coefiicient of about 11,650. In the infrared, maxima are observed at about 5.76, 6.01, 6.12, 6.25, 6.91, 7.01, 7.19, 7.29, 7.38, 7.50, 7.57, 7.90, 7.98, 8.61, 8.94, 9.23, 9.50, 9.83, 10.39, 10.94, and 11.49 microns.

The instant 17a-acetoxy-6-methylenepregn-4-ene-3,20- dione can be prepared also by the substitution of an equivalent quantity of 17oc-acetoxy-3-rnethoxy-6a-methylpregna-3,5-d ien-20-one in the process of this example.

Example 4 By substituting an equivalent quantity of 3-ethoxy-6ozmethyl-17a-propionoxypregna-3,S-dien-ZO-one or 3-methoxy-6 a-methyl-17a-propionoxypregna 3,5 dien-20-one in the process of Example 3, 6-methylene-17a-propionoxypregn-4-ene-3,20-dione is obtained.

Example 5 The substitution of an equivalent quantity of 17a-(2- carboxyethyl)-l7fl-hydroxy-6-methylandrost 4 en-3- one lactone or 21-acetoxy-17a-hydroxy-6-methylpregn-4- cue-3,11,20-trione in the process of Example 1 results androsta-3,5-diene lactone and 21-acetoxy-3-ethoxy-17ahydroxy-6-methylpregna-3,5-diene-3,11,20-trione, respectively.

Example 6 By substituting an equivalent quantity of l7cc-(2-CBI- boxyethyl)-3-ethoxy-17{i-hydroxy 6 methylandrosta- 3,5-diene lactone or 2l-acetoxy-3-ethoxy-l7a hydroxy-6- methylpregua-3,5-diene-3,11,20-trione in the process of monohydrate; This reaction mixture is stirred for about crystallization of the product, which is collected by filtration, washed with cold methanol, and dried to yield 17a-acetoxy-3-ethoxy-6wmethylpregnai,5-die11-20- one, M.P. about 161-168".

By substituting equivalent quantities ofjmethyl orthoformate and methanol in the process of this example, 17u-acetoxy-3-methoxy-6oc methylpregna 3,5 dieu-ZO- one is obtained. r

Example 3, 17a-(2-carboxyethyl) 17,8-hydroxy-6-methylenandrost-4-en-3-one lactone and 2l-acetoxy-l7a-hydroxy-6-methylenepregn-4-ene-3 ,1 1,20-trione, respectively, are obtained.

What is claimed is:

1. A compound of the structural formula wherein R is a lower alkyl'radical.

5 2. 17a-acetoxy-6-methylenepregn-4-ene-3,20-dione. wherein R is a lower alkyl radical, the step which com 3. In a process for the manufacture of compounds of prises eating a compound of {he Structural formula the structural formula CH3 0 I OH:

v ----oo12 1o i R'O 15 wherein R and R are lower alkyl radicals, with manganese dioxide in an inert non-polar organic solvent.

on, No references cited.

. UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 2.980,711 April 18,, 1961 I Frank B. Colton It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 1, for "which" read with column 2, l ne 36, for "acetoxy36" read -acet0Xy3ethoxy-6- line 37, for "-(2carb0xylethyl)-" read (2carhoxyethyl)- Signed and sealed this 17th day of October 1961 (SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Commissioner of Patents Attesting Officer USCOM M-DC 

1. A COMPOUND OF THE STRUCTURAL FORMULA 